CHARACTERISATION OF MANDIBULOACRAL DYSPLASIA (MAD) GENES

Mandibuloacral Dysplasia (MAD;MIM 248370) is a rare autosomal recessive disorder characterized by craniofacial anomalies, severe dental crowding, acroosteolysis, hypoplastic clavicles, atrophy over hands and feet and mottled areas of yperpigmentation. Subjects show loss of subcutaneous fat from the extremities with normal or slight excess in the neck and truncal regions. MAD patients show insulin resistance and its metabolic complications. The disease was described by the Italian paediatrics Cavallazzi in 1963 in an Italian patient showing the typical clinical pictures of MAD. However, the authors erroneously reported this patient as affected by “clediocranialdysplasia”. Eight years, other researchers reported other subjects including the first patient described by Cavallazzi and conied for the first time the term “mandibuloacral dysplasia”. To date about 50 MAD families were reported, 11 of them are of Italian origin. In most of them consanguinity was proved, strongly suggesting the recessive nature of the mutation. We collected 5 consanguineous MAD families and mapped the gene on human chromosome 1 in the region where LMNA/C gene was localized. We defined a “conserved” haplotype that was present in all affected patients and never observed in controls. Sequence analysis of LMNA/C gene revealed a G >A transition at nt 1580 that cause an Arg to Histidine change at amino acid 527 (R527H). We dated the mutation using the “Q method”, calculating the allele frequencies of a marker located outside the disease-bearing haplotype (D1S305) among normal and mutated chromosomes. This analysis has revealed that R527H is originated during the “early middle age”. All Italian MAD families come from a small area of Central Italy, strongly suggesting again the origin of the mutation from a common founder. The complexity of the MAD phenotype suggest that other genes are involved in pathogenesis of the disorder.